1. Field of the Invention
The present invention is concerned with novel N-carboxymethyl substituted lysyl and .alpha.-(.epsilon.-aminoalkyl)glycyl amino acid compounds which are effective inhibitors of angiotensin I converting enzyme. These novel compounds are, consequently, combined with pharmaceutically acceptable carriers to form pharmaceutical compositions of the present invention and are used in a method of treating hypertension.
Angiotensin II, a powerful vasoconstrictor hormonal peptide, is formed from the inactive angiotensin I by the action of angiotensin-converting enzyme. Recently, potent inhibitors of angiotensin-converting enzyme have been reported which are capable of lowering the blood pressure in hypertensive patients. The novel N-carboxymethyl substituted lysyl and .alpha.-(.epsilon.-aminoalkyl)glycyl amino acid compounds of tne present invention are also potent inhibitors of angiotensin-converting enzyme.
2. Brief Description of the Prior Art
U.S. Pat. Nos. 4,113,715; 4,129,571; and 4,154,960 disclose substituted acyl derivatives of amino acids which are useful as angiotension converting enzyme inhibitors. More specifically, these compounds are mercapto substituted acyl amino acids and derivatives thereof including the clinically effective antihypertensive compound, captopril, i.e., D-3-mercapto-2-methylpropanoyl-L-proline.
The foregoing prior art compounds are not dipeptide derivatives as are the compounds of tne present invention. Furthermore, these prior art compounds contain an essential sulfhydryl substituent or derivative thereof whereas those of the present invention do not. In addition, the dipeptide compounds of the present invention are unusual dipeptides whose N-terminus bears a carboxymethyl group which is preferably further substituted on the methyl group. In addition, the carboxyl group(s) may also be converted to ester, amide and salt derivatives. In effect, the compounds of the present invention are hybrids formed by fusing .alpha.-amino acids onto dipeptides by means of a nitrogen shared by these two part-structures. This structural arrangement is rare in the field of synthetic and natural peptides and is not suggested or disclosed by the mercaptoacyl type functions of the two prior art patents identified above.
U.S. Pat. No. 4,052,511 discloses N-carboxyalkanoyl-amino acids which are useful as angiotensin converting enzyme inhibitors. Since the compounds of the present invention are dipeptide derivatives, in a formal sense they may be considered to be related to some of the compounds disclosed in U.S. Pat. No. 4,052,511. However, when a particular one of the methylene groups is replaced by an amino function as in the present invention, compounds of surprisingly high potency are obtained. For example, the preferred compounds of the present invention can be administered in dosages as low as about 2.5 mg per patient per day as opposed to the lowest dosage level of 1 mg per kg per day for preferred compounds disclosed in the U.S. Pat. No. 4,052,511 which is about equivalent to 60 mg per patient per day based on an average patient weight of about 150 pounds.